An experimental Maze Therapeutics drug increased urinary excretion of compounds that are biological indicators of metabolic disease, early clinical trial results that suggest the molecule has best-in-class potential in a rare disorder with few treatment options as well as the opportunity to introduce a new approach to chronic kidney disease.
The placebo-controlled Phase 1 test enrolled 112 healthy adults and evaluated a range of doses of the study drug, MZE782. The main goal was to measure safety and tolerability and the results Maze reported on Sept. 11 showed no serious adverse events or treatment-related complications leading to discontinuation of the study drug. Secondary and exploratory endpoints of the trial included the urine measures as well as measures of kidney function. These are the results that have investors excited.
Maze’s MZE782 is a small molecule designed to selectively inhibit SLC6A19, a gene that codes for a transporter protein that plays a key role in intestinal and kidney absorption and reabsorption of phenylalanine, an amino acid found in certain foods. The rare disease that Maze aims to treat is phenylketonuria, in which phenylalanine builds up in the body and lead to cognitive and behavioral problems. The buildup stems from an inherited deficiency of an enzyme needed to break down the amino acid. Phenylketonuria is primarily managed with dietary changes to limit phenylalanine intake. BioMarin Pharmaceutical markets two FDA-approved medications for the rare disorder.
Phase 1 results for Maze’s drug showed dose-dependent excretion of phenylalanine and glutamine. Maze said higher excretion of those amino acids confirm that MZE782 engaged and inhibited SLC6A19. A single dose of 960 mg of MZE782 led to a 39-fold increase in urinary excretion of phenylalanine over 24 hours. The company also said a 42-fold increase in urinary excretion of the amino acid over 24 hours on day 7 was observed in the group that received the 240 mg dose of the study drug twice daily.
The multiple-ascending cohorts of the study also assessed estimated glomerular filtration rate (eGFR), a measure of how well kidneys filter the blood. MZE782 led to a dose-dependent initial eGFR dip over seven days that was similar in magnitude to what has been observed with SGLT2 and RAAS inhibitors, two classes of drugs currently used to treat chronic kidney disease. Maze said that with other kidney drugs, this initial dip correlates to a slower rate of eGFR decline and better function of kidney function over longer periods of time in chronic kidney disease patients.
With the positive Phase 1 results, Maze said it now plans to advance MZE782 to two proof-of-concept Phase 2 clinical trials. The phenylketonuria study will measure for reductions of phenylalanine in the blood. The chronic kidney disease study will measure reduction in urinary proteins indicative of the disorder. Both studies are expected to begin in 2026.
In a note sent to investors, Leerink Partners analyst Joseph Schwartz said the increase in phenylalanine excretion not only exceeds the goal Maze previously set, it also tops measures achieved by JNT-57, the SLCA19 inhibitor that is the main asset of Jnana Therapeutics. Otsuka Pharmaceutical saw enough promise in this drug candidate to acquire Jnana last year for $800 million up front with another $325 million tied to the achievement of milestones. The Jnana drug is currently in Phase 3 testing in phenylketonuria, but Schwartz sees the Maze drug as a strong contender in that disease as well as chronic kidney disease.
“Overall, these results with Maze’s MZE782 suggest a best-in-class profile, in our view, and we think this program will start to get more credit from investors,” Schwartz said.
Maze followed the data readout with a private placement that raised $150 million from new and earlier investors. The biotech said it would use those proceeds along with its existing capital to finance the planned Phase 2 tests of MAZ782. The capital will also support ongoing Phase 2 testing of Maze’s most advanced program, MZE829, which is in development for treating patients with APOL1-mediated kidney disease.
Image: Getty Images, magicmine
